(Applicant's abstract) Idiopathic pneumonia syndrome (IPS), formerly known as interstitial pneumonitis, accounts for up to 40% of non-GVHD deaths in allogeneic BMT patients. The pathophysiological mechanism(s) responsible for generating IPS are unknown. The applicants' laboratory has established a new murine IPS model which closely simulates the human condition. The severest form of IPS injury in humans occurs with the infusion of allogeneic T cells into recipients of cyclophosphamide (Cy) and total body irradiation (TBI). Therefore, they have constructed a murine model in which Cy/TBI conditioning and allogeneic T cells are used to generate IPS injury and mortality. Their central hypothesis is that these early peri-BMT inflammatory events establish an ideal environment for IPS injury as host MHC class II positive monocytes first are recruited into the lung (day 3), following which donor CD4+ and CD8+ T cells encounter these activated monocytes (Day 7). They will focus upon the early events that initiate lung injury. With respect to the T cell destructive component of IPS, they will determine whether donor T cells cause IPS injury via perforin or cause apoptotic injury via Fas ligand. The induction of endogenous IL-13 is associated with decreased IPS injury will be investigated. The role of IL-13 in downregulating IPS injury by donor T cells. They will explore two roles for these monocytes as: 1. facilitators of cytolytic T lymphocyte generation; 2. effector cells mediating tissue injury. B7 ligand expression is upregulated on host monocytes during IPS injury. Thus, they will use B7 ligand knockout (ko) mice to explore the requirement for B7 ligand expression in the lung for facilitating IPS injury. Their collaborator has shown that monocytes/macrophage secrete macrophage mealloelastase (MME) resulting in the destruction of essential matrix proteins leading to alveolar airspace destruction. They will determine whether MME is upregulated during IPS injury and if so, they will use MME ko recipients to determine whether MME is essential for IPS injury. Chemokines regulate cellular recruitment into damaged tissues. They will explore the critical role of chemokines known to regulate monocyte (MCP-1) and CD8+ T cell (MIP-1 alpha) recruitment in vivo; we will assess the role of proinflammatory T-helper type 1 (CCR5) and anti-inflammatory T-helper type 2 (CCR4) cell recruitment on IPS injury by infusing CC chemokine receptor (CCR) ko donor cells. Because adhesion molecules such as ICAM-1 are known to be critical in recruiting cells in the lung during TBI injury, they will determine whether ICAM-1 is responsible for residual cellular infiltration in the lung when chemokine/receptor interactions described above do not occur. This proposal will provide important new data as to the pathophysiology of IPS injury and may be useful in designing future clinical studies to prevent IPS injury.